Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA.
J Proteomics. 2011 Nov 18;74(12):2691-702. doi: 10.1016/j.jprot.2011.05.013. Epub 2011 May 15.
Aldehyde dehydrogenases (ALDHs) represent large family members of NAD(P)+-dependent dehydrogenases responsible for the irreversible metabolism of many endogenous and exogenous aldehydes to the corresponding acids. Among 19 ALDH isozymes, mitochondrial ALDH2 is a low Km enzyme responsible for the metabolism of acetaldehyde and lipid peroxides such as malondialdehyde and 4-hydroxynonenal, both of which are highly reactive and toxic. Consequently, inhibition of ALDH2 would lead to elevated levels of acetaldehyde and other reactive lipid peroxides following ethanol intake and/or exposure to toxic chemicals. In addition, many East Asian people with a dominant negative mutation in ALDH2 gene possess a decreased ALDH2 activity with increased risks for various types of cancer, myocardial infarct, alcoholic liver disease, and other pathological conditions. The aim of this review is to briefly describe the multiple post-translational modifications of mitochondrial ALDH2, as an example, after exposure to toxic chemicals or under different disease states and their pathophysiological roles in promoting alcohol/drug-mediated tissue damage. We also briefly mention exciting preclinical translational research opportunities to identify small molecule activators of ALDH2 and its isozymes as potentially therapeutic/preventive agents against various disease states where the expression or activity of ALDH enzymes is altered or inactivated.
醛脱氢酶（ALDHs）是 NAD（P）+依赖性脱氢酶大家族的成员，负责将许多内源性和外源性醛不可逆地代谢为相应的酸。在 19 种 ALDH 同工酶中，线粒体 ALDH2 是一种低 Km 酶，负责代谢乙醛和脂质过氧化物，如丙二醛和 4-羟基壬烯醛，两者都具有高度反应性和毒性。因此，ALDH2 的抑制会导致乙醇摄入和/或暴露于有毒化学物质后乙醛和其他反应性脂质过氧化物水平升高。此外，许多东亚人携带 ALDH2 基因的显性负突变，ALDH2 活性降低，患各种类型癌症、心肌梗死、酒精性肝病和其他病理状况的风险增加。本综述的目的是简要描述线粒体 ALDH2 的多种翻译后修饰，例如暴露于有毒化学物质或在不同疾病状态下，以及它们在促进酒精/药物介导的组织损伤中的病理生理作用。我们还简要提及激动人心的临床前转化研究机会，以确定 ALDH2 及其同工酶的小分子激活剂，作为治疗/预防各种疾病状态的潜在药物，这些疾病状态中 ALDH 酶的表达或活性发生改变或失活。
